The present invention relates to the field of implant materials for restoring bone tissues in humans or animals. More specifically the invention relates to a new, easily and consistently applicable composition suitable for restoring bone tissue in a human or animal body, to a method of preparing said composition, to uses of the same as well as to an implant product obtainable from said composition.
The repair and reconstruction of osseous defects have long been a serious challenge to the skills of orthopedic and maxillofacial surgeons.
In order to restore form and function to patients, repairing bone defects presently involves several surgical techniques. However, although effective in many cases, the existing technology has numerous difficulties and disadvantages.
Therefore the implantation of materials of different types in the human or animal body in order to replace bone portions which have been traumatized or which have deteriorated due to diseases is steadily increasing. In order to eliminate the risk of having immunological or infectious diseases and to avoid operations on several sites, different synthetic materials have come into use within this technical field. As examples of suitable materials used for said purpose there can be mentioned minerals and ceramics such as tricalcium phosphate and calcium aluminate. Especially preferred materials are, however, materials having a chemical composition and crystal structure similar to those of the materials that are built up by the living organism, such as calcium hydroxy-apatite. One synthetic material of this type which has come into use for restoring bone tissue is the mineral calcium hydroxyapatite and is available both as blocks of different shapes and granules of different sizes.
Commercial hydroxyapatite is supplied by many producers. Thus, for instance, hydroxyapatite of the above-mentioned formula is manufactured by Asahi Optical Co., Ltd., Tokyo, Japan, Interpore Int. Irvine, Calif., USA, and Impladent Ltd., Holliswood, N.Y., USA. The material is available both as resorbable and as non-resorable hydroxyapatite granules/particles for different applications.
In most cases the above-mentioned granules or particles are mixed with blood or a physiological saline solution in order to obtain a mass that is easier to apply to the desired site of the bone, when applying said granules or particles to the bone. A major drawback to this materia or technique is, however, that such a mass is not easily properly confined within the bone cavity referred to. Furthermore, when the mass has been applied to the bone, blood that may come from adjacent bleeding portions of the body or any other secreted body fluid will dilute the particulate mass and may even carry away the material from the site of application.
Attempts to solve these problems have been made, as is for instance disclosed by Alper G. et al. in The American Journal of the Medical Sciences, December 1989 (298): 371-376. However, said reference clearly shows that generally a moldable hydroxyapatite system based on phospholipid and added stearic acid does not stimulate new bone formation or conduct bone growth but rather demonstrates a decrease in bone formation.
Furthermore, since liposomes, which are spherical particles consisting of closed bilayers with water inside as well as outside thereof, have a membrane structure similar to matrix vesicles, Huang et al. have suggested, in Kao Hsiung I Kaohsiung J.Med.Sci. 1997, 13:213-228, that negatively charged liposomes might improve the nucleation process for new bone formation. This concept was tested in a mandibular defect of miniature swine but was not confirmed. Thus, they found that when comparing the bone development of pure calcium phosphate with liposome-coated calcium phosphate the pure implanted material had better and more mature bone tissue development and that the amount of bone tissue was greater than for the implanted material coated with liposomes.
Phospholipids have also been used to produce sustained release formulations of drugs from ceramic granules as is e.g. disclosed in Japanese Patent No. 2,198,560. Antibiotic-loaded hydroxyapatite has been of especial interest since local infections of the operating site is a potential complication. (Df. Yamamura K et al., Journal of Biomedical Materials Research, Vol. 26, 1053-1064 (1992), and Shinto Y. et al., J. Bone Joint Surg., 1992 (74):600-604).
Finally, as concerns implant compositions, reference is also made to EP 0 429 419, which discloses a system where calcium phosphate, and especially hydroxyapatite, is used as a bone tissue substitute material. However, in said case no phospholipid is used but rather a monoglyceride as the basis for the carrier. Furthermore, as in all other cases represented by the prior art, the carrier is not of the same nature as the carrier according to the present invention. Thus, as will be described below the composition according to the present invention as based on a lamellar liquid crystalline phase used as such for the bone formation step. Contrary thereto, EP 0429 419 relies on the use of a phase conversion from an L2-phase into a harder cubic liquid crystalline phase or reversed hexagonal liquid crystalline phase for the bone formation step. In the present case the composition of the lamellar liquid crystalline phase is such that no phase conversion takes place if adding further water. Rather, it is even possible that addition or presence of body fluid after the composition has been implanted promotes the dispersion of the lamellar liquid crystalline phase and the removal of the same from the implant site to thereby enhance the healing process by exposing a bioactive hydroxy-apatite surface to the cells.
The primary object of the present invention is to overcome the drawbacks referred to above and to provide an implant material which can be easily and consistently be applied to the desired site of action, i.e. where the bone tissue restoration is to be made. More specifically, this means that the new implant material according to the present invention is capable of resisting dilution and any forces tending to carry away the material from the place of application.
Furthermore, the bone restoration properties as well as the biocompatibility of the new composition according to the present invention has been found to be outstanding as compared to other, previously known systems.
According to the present invention it has been found that the objects referred to above can be achieved by providing a composition wherein a solid calcium phosphate is used as a biocompatible bone tissue substitute material which is distributed in a lamellar liquid crystalline phase comprising at least one phospholipid and water or other aqueous liquid as a bioacceptable carrier therefor. Thus, by using a calcium phosphate, and especially hydroxyapatite, as the main or only bone tissue substitute material in combination with phospholipid(s) in the form of a specific phase, i.e. a lamellar liquid crystalline phase, an implant composition is achieved, the properties of which are outstanding relative to previously known compositions in this field.
In addition to what has been disclosed above concerning advantages of the present invention, it could be added that other previously tested gel systems show several disadvantages. Thus, for instance a water-based gel-like hyaluronic acid is rapidly dehydrated, which means that the consistency thereof varies under the use thereof. This in turn means than it is much more difficult to shape and handle than the composition according to the present invention. The use of proteins like collagen from animals can impart undesirable immunologic reactions, while the use of two component gel systems is a complicated procedure requiring the mixing and curing of two ingredients during a limited time.
Moreover, it should be noted that the composition according to the present invention has been found to show a high amount of newly formed bone while staying very well in the defect tested. Contrary thereto, when using hyaluronic acid as a carrier granules were found outside the tested bone defect, i.e. in soft tissue, where also inflammatory cells were found. It is previously known that particles of calcium phosphate in soft tissue can cause an undesirable cell reaction which does not take place when the granules are present in the bone.
More specifically, the new composition according to the present invention, suitable for restoring bone tissue in a human or animal body, comprises a solid, preferably particulate, calcium phosphate as a biocompatible bone tissue substitute material distributed in a lamellar liquid crystalline phase of at least one phospholipid and water or other aqueous liquid as a bioacceptable carrier therefor, said lamellar liquid crystalline phase being pre-formed or being formed in situ in said body in the presence of said water or other aqueous liquid.
Expressed in another way, the present invention relates to a composition suitable for a composition suitable for restoring bone tissue in a human or animal body, comprising a solid, preferably particulate, calcium phosphate as a biocompatible bone tissue substitute material distributed in a bioacceptable carrier therefor, wherein said bioacceptable carrier comprises at least one phospholipid and water or other aqueous liquid, e.g. body fluid, said at least one phospholipid being present in such amount that a lamellar liquid crystalline phase is formed when providing said water or other aqueous liquid either in a pre-forming operation outside said body or in situ in said body.
In other words, according to one alternative, the lamellar liquid crystalline phase referred to is preformed before being used in a human or animal body for restoring bone tissue therein. According to another alternative said lamellar liquid crystalline phase is formed in situ in said body in the presence of water or other aqueous liquid. In the latter case said water or other aqueous liquid can be added to the site of reaction in the body or being supplied thereto from the body, i.e. in the form of any body fluid (including blood), or a combination thereof. In connection with these alternatives it should thus be noted that the phospholipid(s) are used in such amount(s) that said lamellar liquid crystalline phase can be formed under the circumstances prevailing in each specific case. That is, the composition to be used in any specific case can easily be taken from a common phase diagram for the ingredients used.
The calcium phosphate used as bone tissue substituted material can be chosen according to known principles concerning biocompatible calcium phosphates. Thus, it may be of the resorbable or the non-resorbable type. However, according to a preferable embodiment of the invention a calcium phosphate is utilized which has a molar ratio of Ca:P of from 1:1 to 2:1, preferably from 1.5:1 to 1.7:1. An especially preferable calcium phosphate of this type is calcium hydroxyapatite, most preferably a hydroxyapatite of the formula Ca10(PO4)6(OH)2.
As has been mentioned already above the solid calcium phosphate is preferably used in the form of particles, especially granules, a preferable size thereof being from 0.05 mm to 5 mm, expressed as an average diameter thereof.
The calcium phosphate used in accordance with the present invention can be a porous or dense material. However, it has been found that the use of a porous material instead of a dense one may have certain advantages, e.g. by allowing an ingrowth of bone tissue which seems to lead to a more complete and rapid stabilization of the bone tissue substitute material at the recipient site. An especially preferable porosity in this respect is in the range of 20 to 80%.
As mentioned, the calcium phosphate is the major, or only, bone tissue substitute material of our composition. However, one advantageous embodiment of the invention is represented by the case where the composition also contains natural bone, i.e. of human or animal origin. For obvious reasons such bone is preferably taken from the human being or animal involved in the bone tissue restoring procedure, such as bone granules or particles obtained when e.g. drilling a bone cavity in connection with a bone tissue restoring operation of the type referred to.
Contrary to what is disclosed in prior art it has also been found especially preferable in connection with the present invention to use a phospholipid which is substantially neutral, i.e. non-charged, under physiologically conditions. Expressed in another way this means that in accordance with the present invention the phospholipid is preferable used alone, i.e. for instance without any added stearic acid or other acid compound as in connection with some prior art.
Generally the phospholipid carrier is selected from the group consisting of glycerophospholipids and sfingolipids. The acyl groups of such glycerophospholipids and/or sfingolipids, which groups may be the same or different, are each preferably derived from a saturated or unsaturated fatty acid having 14-22 carbon atoms, especially 16-20 carbon atoms. More preferably said fatty acid is a fatty acid having 16 or 18 carbon atoms, especially an unsaturated (including mono- or polyunsaturation) fatty acid having 18 carbon atoms. Most preferable in this respect is oleic acid and/or linoleic acid, preferably oleic acid.
The phospholipid referred to can of course be an entirely synthetic product but can also be derived from a natural product in the form of a vegetable or animal raw material. Examples of such raw materials are a vegetable oil or egg yolk, such as soy bean oil, rape-seed oil, etc.
Preferred examples of glycerophospholipids are such which are derived from lecitines. Especially preferred is phosphatidylcholine.
An especially preferred sfingolipid is sfingomylein, which is also based on choline. A specific group of phospholipids is diacylphosphatidylcholines.
A further preferable embodiment of the composition claimed is a composition wherein the phospholipid carrier also contains an antioxidant, which can be selected among known antioxidants in accordance with principles known per se. However, an example of an advantageous antioxidant in this respect is tocopherol.
The exact ratios between the ingredients in the composition of the invention are dictated by the fact that a lamellar liquid crystalline phase is to be created and utilized. Therefore, the exact compositions to have the desired phase can easily be determined by a person skilled in the art, for instance by means of a phase diagram for the specific ingredients used. However, preferable embodiments with reference to such compositions are the following.
A preferable weight ratio of calcium phosphate to phospholipid is within the range of 70:15 to 60:40.
The weight ratio of phospholipid to water or other aqueous liquid is generally within the range of 1:2 to 10:1, preferably 3:2 to 4:1
With reference to the aqueous liquid utilized to form the lamellar liquid crystalline phase referred to it can, thus, be water or any other aqueous liquid by means of which said phase can be formed. Preferably pure water, an isotonic salt solution or a pharmaceutically acceptable buffer is utilized, but if advisable for any reasons, e.g. in the case where said phase is formed in situ, any aqueous body fluid, including blood, may be used.
According to a second aspect the present invention also relates to the composition as defined above, also with reference to all preferable embodiments thereof, for use as an implant material composition for restoring bone tissue in a human or animal body.
Furthermore, the invention relates to the use of the above-mentioned composition for the manufacture of a product to be used as an implant material for restoring bone tissue in a human or animal body. All preferable embodiments described above in connection with the implant material composition are equally applicable to this aspect of the invention.
Expressed in another way the invention also relates to a method of restoring bone tissue in a human or animal body, which comprises contacting the composition as defined above with a bone cavity of a human or animal body in need thereof, in order to restore said bone tissue.
Still another aspect of the invention is represented by a method of preparing the above-identified implant material composition. Also in this context all preferable embodiments thereof are included.
Said method comprises either
a) creating said lamellar liquid crystalline phase from said phospholipid(s) and said water or other aqueous liquid and distributing said calcium phosphate bone tissue substitute material therein; or alternatively
b) pre-forming an admixture of said phospholipid(s) and said calcium phosphate bone tissue substitute material in such proportions that said lamellar liquid crystalline phase will be created in situ in the human or animal body when providing said water or other aqueous liquid thereto.
Thus, according to the first alternative the lamellar liquid crystalline phase to be used in accordance with the invention is created outside the body, while according to the second alternative a pre-mixture is formed outside the body, said pre-mixture having such a composition that when used later on for the intended purpose the desired lamellar liquid crystalline phase is created in situ.
As concerns the second alternative referred to the method of restoring bone tissue in a bone of a human or animal body thus comprises applying said pre-mixture to the surface of any bone or bone cavity defect where lost bone tissue is to be restored and allowing said composition to come into contact and/or contacting the same with water or other aqueous liquid in such an amount that the desired lamellar liquid crystalline phase is created.
With reference to the term xe2x80x9cdistributingxe2x80x9d the calcium phosphate bone tissue substitute material in the lamellar liquid crystalline phase, or similar, said term should be interpreted in a broad sense and generally means spreading out in any manner throughout said phase. Expressed in another way the bone tissue substitute material can be said to be dispersed or slurried in the phase referred to.
A preferable embodiment of alternative b) of the method according to the invention is represented by the case where said admixture is formed in the presence of a liquid enabling the manufacture of a sterile lipid solution, which is preferably spread onto said calcium phosphate material, said liquid being then removed by freeze-drying or lyophilization. An example of such a liquid is represented by a lower alkanol, ehtanol being especially preferred.
Finally, the invention also relates to the restored implant bone tissue product per se, i.e. the product which is obtainable by contact between the composition as defined above and body fluid, optionally with added aqueous liquid.
As was mentioned above one major advantage of the present invention is that the new composition is extremely easy to shape and handle and that particles thereof are fully or at least substantially completely prevented from escaping from the application site. Thus, if this would happen, the particles could cause irritation or complication at other places of the body.
Other advantages could be gathered from the present specification or should be obvious to a person skilled in the art after having read the present specification.
In connection with the invention the term xe2x80x9cbiocompatiblexe2x80x9d is used, which term has the common meaning that it must not cause any significant side effects in contact with living cells or organisms. Also rheological considerations should be made to make sure that the required phase is adapted for use in contact with the human or animal body, i.e. at temperatures at or around normal body temperature, e.g. at most 40xc2x0 C.
The use of the composition claimed in the intended implant procedure will follow the general principles in this technical field and need not be described further here.